Diabetes mellitus is the disease which fails to utilize glucose in the body sufficiently. It follows that increases of blood glucose level or chronic hyperglycemia are caused and various complications are induced. It is absolutely important to normalize blood glucose levels in the treatment of diabetes. For the purpose, parenteral administration of insulin (the hormone which regulates blood glucose), oral administration of drugs and dietary therapies have now been carried out. Diabetes mellitus is classified into two major forms of type I diabetes and type II diabetes.
Type I diabetes is the result of a deficiency of insulin; which is basically improved by administration of insulin. On the other hand, type II diabetes, which is insulin-independent diabetes, occurs in the face of normal or even elevated levels of insulin. This means that the tissue response to insulin is impaired. In the treatment of type II diabetes, oral administration of drugs which promote insulin secretion or repress absorption of sugar containing in the diet, parenteral administration of insulin and dietary therapies have been carried out. However, these are not fundamental methods for the treatment of diabetes, and patients frequently suffer from side effects and pains. Therefore, it has been desired to develop drugs improving pathosis of diabetes. In addition, most of the type II diabetes are also associated with obesity which is closely related to occurrence of diabetes. It is known that in a patient suffering from diabetes and obesity, diabetes is improved by healing obesity.
Obesity is thought to be caused by accumulation of fat in the body, and in order to improve obesity, it is necessary to consume fat. Recently, obesity or diabetes has become a problem in pets as well as humans due to excess nutrition and lack of exercise. Additionally, it has been desired to decrease fat and increase lean meat of edible animals.
It is known that .beta.-adrenergic receptors are divided into .beta.1, .beta.2, and .beta.3-subtypes. Stimulation of .beta.1 receptors mainly causes increase in heart rate. Stimulation of .beta.2 receptors mainly causes bronchodilation and smooth muscle relaxation. Stimulation of .beta.3 receptors mainly promotes lipolysis (the breakdown of adipose tissue trigylcerides to glycerol and free fatty acids) and energy consumption, by which the decrease in fat mass is invoked. Accordingly, it is thought that compounds having .beta.3 agonistic activity possess anti-obesity activity. It is reported that these compounds have anti-hyperglycemic activity in animal models of type II diabetes. These indicate that .beta.3 agonists are useful in improving obesity in mammals and hyperglycemia in diabetes of mammals.
Compounds below are known as main .beta.3 agonists.
Ainsworth et al., in Japanese Patent Kokai 56-5444, disclose a compound (BRL 37344) of the following formula (XVI) ##STR3## and its carboxylic acid methyl ester (BRL 35135) or a pharmaceutically acceptable salt thereof. These compounds have anti-obesity activity and anti-hyperglycemic activity. BRL 35135 has also lipolytic activity (.beta.3) in rats (Nature, Vol. 309, 163, 1984). Effects on .beta.3 adrenergic receptors show that these compounds are useful as anti-obesity drugs. Further, it is reported that these compounds have anti-hyperglycemic activity in animal models of type II diabetes. The treatment for diabetes or obesity using .beta.3 agonists has disadvantages of possibility of stimulating other .beta. receptors and side-effects resulting therefrom. They are, for example, muscle tremor caused by stimulating .beta.2 receptors and increase in heart rate caused by stimulating .beta.1 receptors. BRL 35135 has .beta.3 agonistic activity, but, at the same time, it has .beta.1 or .beta.2 agonistic activity, which is thought to cause such side-effects.
Bloom et al., in Japanese Patent Kokai 5-320153, disclose a compound (CL 316243) of the following formula (XVII) ##STR4## wherein R is a carboxy group, an alkoxycarbonyl group or a salt thereof.
Epstein et al., in Japanese Patent Kokai 7-2831, disclose a compound of the following formula (XVIII) ##STR5## wherein R is a carboxy group, an alkoxycarbonyl group or a salt thereof. The above-mentioned compounds have greater agonistic activity to .beta.3 than to .beta.1 and .beta.2, with the selectivity. The compounds of the above-mentioned formulae (XVII) and (XVIII) have .beta.3 agonistic activity in the experiment using rodents, in particular rats, but .beta.3 agonistic activity in human is still unknown.
Recently, the methods for estimating the activity in human more exactly have been developed. Human .beta.3 agonistic activity can be determined by using the cloned human .beta.3 receptors which are expressed in the neuroblastoma cells and measuring the increase of cAMP production according to these analysis. The agonistic activity of various compounds to this cultured cells offers the index of human .beta.3 agonistic activity (Molecular Pharmac., Vol. 42, 753, 1992).
.beta.3 agonists are useful as anti-obesity drugs or anti-diabetes drugs, while the number of patients with obesity or diabetes tends to increase every year. Therefore, it has been desired to develop compounds having a chemical structure different from known .beta.3 agonists and having distinct human .beta.3 agonistic activity.